Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
31.25
Modified dose descriptor starting point:
NOAEC
DNEL value:
105.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
1-chlorobutane is assumed to be readily absorbed gastrointestinally like the structural analogue 1-butanol. The inhalatory absorption is regarded to be equivalent to the oral absorption.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable. Please also refer to the discussion.
AF for differences in duration of exposure:
1
Justification:
No conversion AF is needed as the starting point is a chronic study. Please also refer to the discussion.
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.
AF for intraspecies differences:
5
Justification:
Default AF for the worker.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient and uncritical.
AF for remaining uncertainties:
2.5
Justification:
An additional assessment factor for remaining uncertainties is applied. Please also refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.96 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
125
Modified dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
According to QSAR predictions obtained from the Danish (Q)SAR database (2010), dermal uptake is predicted to be moderate (0.021 mg/cm²/event). Based on this, a dermal uptake of 50% is assumed.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable. Please also refer to the discussion.
AF for differences in duration of exposure:
1
Justification:
No conversion AF is needed as the starting point is a chronic study. Please also refer to the discussion.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for differences between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There is no evidence for species differences in the general mode of action or kinetics. However, standard AF is applied.
AF for intraspecies differences:
5
Justification:
Default AF for the worker.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient and uncritical.
AF for remaining uncertainties:
2.5
Justification:
An additional assessment factor for remaining uncertainties is applied. Please also refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Workers might be exposed to limited quantities of 1-chlorobutane during manufacture, formulation, processing or filling in appropriate containers via dermal contact or by inhalation.

Since no dose descriptors for the dermal and inhalation exposure route are available, the only usable dose descriptor (oral route) to derive systemic long-term DNELs, the dermal as well as inhalation DNELs, regarding long-term effects on workers were determined using route-to-route extrapolation, according to the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

In the data set for 1-chlorobutane, there are several studies which are considered for derivation of long-term DNELs.

In the data set for 1-chlorobutane is a Japanese reproduction toxicity screening study equivalent to OECD TG 421. In this study rats were administered 1-chlorobutane orally and the possible effects on reproduction were investigated. From observation of the mother animals during the lactation period, there was nothing of note in the control group and the 2.4 mg/kg bw/day group. On the other hand, poor nursing behaviour, including underdevelopment of nipples and "off-nesting (no feeding)" was observed in one dam in the dose group of 12 mg/kg bw/day (Day 0, 1 and 2 of lactation), in one dam in the group of 60 mg/kg bw/day (Day 1 and 2 of lactation), as well as in one dam in the dose group of 300 mg/kg bw/day (Day 3 and 4 of lactation). No clear dose response relationship was observed for this finding. Epidermal temperatures were lowered in the offspring of one dam in each of the 12 and 60 mg/kg bw/day dose group and two dams in the 300 mg/kg bw/day dose group and the body weight of the respective offspring decreased compared to other offspring in the same group. One dam of the high dose group died on the fourth day of nursing and it was thought that the other dam could not adequately lactate and this resulted in an abnormality and the display of poor nursing behaviour. There were a large number of offspring deaths by the fourth day of nursing in the 300 mg/kg group, including these two cases, and, the survival rate was reduced on the Day 4 of lactation, but not statistically significant. Survival rates were decreased in the offspring of the 12 and 60 mg/kg bw/day groups, however, the decrease was not statistically significant. In general, interpretation of the study report is difficult as there is no clear differentiation between No-Observed-Effect-Levels and No-Observed-Adverse-Effect-Levels. The authors of the study were of the opinion that the finding of salivation, which occurred at all dose levels, was a sign of substance-related toxicity. However, salivation was observed about 2 to 5 minutes after administration and continuing until 30 minutes to one hour after administration and is therefore very likely due to the dosing procedure (gavage) in particular if the test item is irritating or unpalatable. In the summary of the report it is stated that the general toxicological no-observed-effect-level for both males and females is below 2.4 mg/kg bw/day (salivation), while possibly treatment-related maternal toxicity at 12 mg/kg bw/day in the lactation period and at 300 mg/kg bw/day in the perinatal period occurred in the context of reproductive toxicity. In the conclusion the authors of the study stated that the dose level without toxic effect (NOEL) to reproduction was 300 mg/kg bw/day for males (no effects at the highest dose level tested) and 2.4 mg/kg bw/day for females and 60 mg/kg for offspring. Although the Japanese reproduction toxicity screening study is suitable to provide some evidence for the absence of teratogenicity and for the absence of fertility impairment following exposure to 1-chlorobutane, the study remains questionable with regard to the interpretation of the toxicological relevance of findings and the reporting of the relevant effect levels. Based on these arguments this study is considered NOT to be the most suitable one from the data set as point of departure for derivation of long-term worker DNELs.

The NTP study package dated 1986 includes a valid subchronic toxicity part as well as a valid 2-year carcinogenicity part, each part conducted in two species, rat and mouse. The NTP study was also reviewed in the OECD SIDS report. The NOAEL for subchronic repeated dose toxicity in rats is considered to be 120 mg/kg bw/day, in mice 500 mg/kg bw/day, respectively. In the carcinogenicity study in the rat the NOAEL based on toxicity was 60 mg/kg bw/day, in mice 500 mg/kg bw/day, respectively.
The registrant decided to use the NOAEL of 60 mg/kg bw/day for toxicity from the NTP carcinogenicity study in the rat as the most relevant point of departure for DNEL derivation considering the following aspects:
1) The NTP carcinogenicity study with 1-chlorobutane is the study available with the longest exposure duration of 2 years. As the DNELs derived are supposed to cover chronic worker exposure to 1-chlorobutane it is reasonable to use the study with the longest duration of exposure predicting effects which may occur following a maximum exposure period. Using the study with the highest predictivity for long-term worker exposure is considered to be the most adequate approach and sufficiently conservative.
2) The chronic exposure to 1-chlorobutane has been evaluated in two species in the NTP study. The resulting No-Observed-Adverse-Effect-Level from the carcinogenicity study in the rat is lower than the respective NOAEL in the mouse. Thus, the NOAEL from the rat study is selected as point of departure. Due to selection of the most sensitive species the approach is conservative.
3) The relevance of high dose effects observed in an animal study with regard to the worker needs be taken into account when selecting an appropriate point of departure for derivation of DNELs. Behavioural changes leading to a decreased maternal care and in the consequence to a distinct adverse outcome for the offspring were seen in the high dose females in the Japanese reproduction and developmental screening test. This finding is without any doubt an adverse finding no matter if it is substance-related or not. However, the relevance of this finding for the worker needs to be critically considered as the finding occurred at a dose level where direct maternal or postnatal toxicity for the offspring is absent. Also no teratogenic effects were identified in the offspring at the dose level of 2.4 mg/kg bw/day or any level above. It can be assumed that the NOAEL for direct toxicity for the offspring is above 2.4 mg/kg bw/day, i.e. in the same range as maternal toxicity above 60 mg/kg bw/day which is in accordance with the conclusion of the study authors. The decreased maternal care is an indirect effect on the offspring. As the indirect causality of decreased maternal care is not relevant for the worker (the worker neither has the sensitivity of a newborn nor is dependent on maternal care), also from this study the relevant point of departure would need to be based on direct toxicity. The lack of maternal care might be also related to other factors than substance-related toxicity (underdevelopment of nipples is mentioned for the dams). Furthermore a clear dose-response relationship for the decreased maternal care is missing. In conclusion, an unreflected transferability of the decreased maternal care to the workplace situation is not reasonable in the context of DNEL derivation.
4) The consistency of the data base with regard to the dose response relationship needs to be considered for DNEL derivation. Based on body weight depression and convulsions at the dose of 250 mg/kg bw/day in the NTP 90-day repeated dose toxicity study in the rat, the NOAEL of this study was set to 120 mg/kg bw/day. In accordance to this outcome in the Japanese reproduction toxicity screening study (dosing period 49 days for males and 41-46 days for females) the NOAEL for maternal toxicity was set to 60 mg/kg bw/day based on reduced body weight and food consumption at 300 mg/kg bw/day. Also in the NTP carcinogenicity study an NOAEL of 60 mg/kg bw/day was obtained following 2 years of exposure. Convulsion and tremors after dosing especially in high dose animals were common throughout the 2-year gavage study in rats. These central nervous effects have to be seen in connection with the application technique (bolus administration, gavage). Since it may be assumed, that 1-chlorobutane is readily absorbed like the structural analogue 1-butanol, bolus administration (gavage) of 1-chlorobutane may lead to a high and short-term peak concentration. In contrast, inhalation of 1-chlorobutane may result in a uniform flow until steady-state conditions are achieved, whereby no peak levels occur (TRGS 900). This assumption is confirmed by an acute inhalation toxicity study (Study director, 1990), in which no central nervous effects were observed. The dose-response relationship of the data set is considered consistent.
5) Although of highly questionable relevance for the worker, in order to address remaining uncertainties related to the decreased maternal care occurring in the Japanese reproduction toxicity screening study in a sufficiently conservative manner, an assessment factor of 2.5 is applied for derivation of long-term worker DNELs.
6) In view of an overall assessment factor of 32 for the inhalation route (an additional factor for allometric scaling of 2.6 is already included in the corrected point of departure, i.e. actual overall assessment factor is 84) and 125 for the dermal route (calculations see below) the overall assessment is considered sufficiently conservative to protect the worker.

As discussed above, for the derivation of all DNELs, the NOAEL of 60 mg/kg bw/day obtained in the 2-year gavage study in rats (testing concentrations: 0, 60 and 120 mg/kg bw/day) performed by NTP (1986), which is in the same dose range as the maternal systemic NOAEL of 60 mg/kg bw/day seen in the Japanese reproduction toxicity screening study, was selected as dose descriptor starting point taking into account remaining uncertainties arising from the latter study.

 

The conversion of an oral NOAEL into an inhalation NOAEC is performed using the following equation:

For workers (light activity):

Corrected inhalatory NOAEC = oralNOAEL x 1/sRVanimal x ABS oral / ABS inhalation

The standard respiratory volume (sRV) for the 8 h exposure is 0.38 m³/kg bw for rats and 6.7 m³ (per person) in humans. The default 8-h respiratory volume of a worker is 10 m³ taking increased activity into account. The inhalatory absorption is regarded to be equivalent to the oral absorption.

This results in the following equation:

Corrected inhalatory NOAEC = 60 mg/kg bw x (1/0.38 m³/kg bw) x (6.7 m³ / 10 m3) = 105.8 mg/m³

In order to derive the long-term inhalation DNEL an overall assessment factor of 32 is applied to the corrected dose descriptor:

DNEL long-term inhalation= 105.8 mg/m³/ (1 (dose response relationship) x 1 (duration of exposure ) x 1 (interspecies differences (allometric scaling)) x 2.5 (other interspecies differences) x 5 (intraspecies differences) x 1 (quality of whole database) x 2.5 (remaining uncertainties) =3.4 mg/m³

To convert an oral NOAEL (in mg/kg bw/d) into a dermal NOAEL, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. According to QSAR predictions obtained from the Danish (Q)SAR database (2010), dermal uptake is predicted to be moderate (0.021 mg/cm²/event). Based on this, a dermal uptake of 50% is assumed.

The conversion of the oral NOAEL into the dermal NOAEL is performed using the following equation:

Corrected dermal NOAEL = oral NOAEL x ABS oral / ABS dermal = 60 x 1/0.5 = 120 mg/kg bw/day

In order to derive the long-term dermal DNEL an overall assessment factor of 125 is applied to the corrected dose descriptor:

DNEL long-term dermal= 120 mg/kg bw/day / (1 (dose response relationship) x 1 (duration of exposure) x 4 (interspecies differences (allometric scaling)) x 2.5 (other interspecies differences) x 5 (intraspecies differences) x 1 (quality of whole database) x 2.5 (remaining uncertainties)) =0.96 mg/kg bw/day

 

References:

BAUA: Begründung zu 1-Chlorbutan in TRGS 900, Ausgabe Januar 2006

ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012

OECD SIDS Initial Assessment Report for SIAM 6, Paris, France, 9-11 June 1997

The final report of “Simple Reproduction and Development Screening Test for Oral Administration of 1‐Chlorobutane (CAS No. 109693) in Rats” (Test number: NBR-1) (Japan Bio Research Center, Haneshima Research Facility, 1993), English translation

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Since exposure for the general public is precluded, DNELs for the general population are not relevant and thus not derived.